In the recent years increasing evidence of the advantages of reduced folate vs folic acid have been found. The rational use of reduced folate (particularly reduced and methylated such as Quatrefolic®) is derived from the inability of a part of world population to assimilate and metabolize folic acid from food or supplements (the most of folate assumption is coming from folic acid man-made version in supplements and added to foods).
Folic acid and also food folate are not biologically active and need to be converted to the metabolically active 5-methyltetrahydrofolate (5-MTHF) through a multi steps process where the enzyme methylenetetrahydrofolate reductase (MTHFR) owns a key role. Some individuals, due to their unique genetic patterns and expression, have polymorphic forms of this enzyme and do not produce adequate or effective MTHFR [1, 2, 3].
Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes in human physiology, deficiencies in production or function of this enzyme have been associated with increased risk of different diseases [9, 1].
These defects related to MTHFR are very common, though they vary enormously between ethnic groups and regions [10, 11]. Emerging science of nutrigenomics indicates that MTHFR most often refers to a genetic mutation that inhibits the ability of the body to methylate (or convert folic acid from the food we eat into the metabolite we need, L-5-Methyltetrahydrofolate) so as some individuals cannot actually use folic acid [12]. Cutting-edge scientific research is shed light how much the MTHFR polymorphism is implicated in chronic disease states and how folate nutrition may contribute to replace adequate methylation and overall health [9]. The other advantage is that Quatrefolic® passes the gastric barrier and is absorbed mainly in the small intestine by a carrier mediated mechanism. The carrier is not saturated and this enables Quatrefolic® to ensure a higher folate uptake [1, 4].
Since the implementation of folic acid fortification programs, several studies have reported increased circulating levels of unmetabolized folic acid (UMFA) in serum, raising questions regarding excessive intake and the body’s metabolic capacity to fully process synthetic folic acid [5–8]. Folic acid must undergo multiple enzymatic reduction steps, primarily through dihydrofolate reductase (DHFR), before conversion into the biologically active form, 5-methyltetrahydrofolate (5-MTHF). However, DHFR activity in humans is relatively limited and highly variable among individuals. When intake exceeds the body’s metabolic capacity, unmetabolized folic acid may accumulate in circulation as UMFA [13–15].
The persistence and variability of UMFA levels within the population may be influenced by several factors, including genetic polymorphisms affecting folate metabolism (such as MTHFR variants), impaired folate reduction pathways, liver dysfunction, chronic inflammation, and high intake from fortified foods and dietary supplements containing folic acid or folate [13–15].
Recent findings from the Frontiers in Nutrition study further demonstrated that supplementation with folic acid resulted in significantly higher serum UMFA concentrations compared with supplementation using 5-MTHF glucosamine salt. The study also observed a substantially greater proportion of individuals reaching supraphysiological folate concentrations in the folic acid group, while the 5-MTHF group maintained comparable folate status with markedly lower UMFA exposure [16]. These findings support the concept that active folate forms may provide more physiologic folate delivery while minimizing accumulation of unmetabolized folic acid.
Quatrefolic®, The InnovActive Folate Everyone Can Benefit From
Quatrefolic® by Gnosis by Lesaffre answers to all consumers’ and physicians’ concerns relating to potentially harmful effects of folic acid administration (pregnancy, infants, homocysteine, …). As Quatrefolic® provides the metabolic reduced folate form utilized and stored in the human body, the (6S)-5-methyltetrahydrofolate, it does not aid to the potential accumulation of UMFA in the blood, which has no biological function and whose effects are not yet known, also due to the potential uncontrolled assumption of folic acid by diet.